Is CRYM p.Ile141Val (c.421A>G) pathogenic?

CRYM p.Ile141Val (c.421A>G) is classified Conflicting classifications of pathogenicity in CRYM (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-10-08). AlphaMissense: likely benign (0.2129); Rare (popmax 0.103%, sas); Associated with autosomal dominant nonsyndromic hearing loss 40.

What condition is associated with CRYM p.Ile141Val (c.421A>G)?

CRYM p.Ile141Val (c.421A>G) is associated with autosomal dominant nonsyndromic hearing loss 40 (ClinVar).

How common is CRYM p.Ile141Val (c.421A>G) in the general population?

CRYM p.Ile141Val (c.421A>G) is rare (popmax 0.103%, sas) (gnomAD).

What do computational predictors say about CRYM p.Ile141Val (c.421A>G)?

AlphaMissense predicts likely benign (score 0.2129) — an in-silico prediction, not a clinical call.

CRYM p.Ile141Val

c.421A>G · rs141595341 · VCV2144479

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2129 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.103%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autosomal dominant nonsyndromic hearing loss 40

Computational evidence

Protein change
AlphaMissense	0.2129	likely benign
REVEL	0.326	indeterminate
SaProt	LLR -9.49	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 19 kb · p 0.0044 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.103% South Asian · 93/90,240 alleles

Filtering AF 0.0861% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0798%

Overall 0.0129% 200/1,553,162 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.103%	970
Middle Eastern	0.0698%	1,432
Remaining individualsnot grpmax-eligible	0.0187%	5,336
European (non-Finnish)	0.00769%	13,001
Admixed American	0.00356%	28,105
African / African-American	0.00283%	35,392

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CRYM
Protein: p.Ile141Val
Coding: c.421A>G
MANE Select: NM_001376256
dbSNP: rs141595341
Type: single nucleotide variant
Location: chr16:21269858 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.06 · 1 PDB
Residue 141: a β-strand

Full CRYM gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal dominant nonsyndromic hearing loss 40 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CRYM p.Val4Leu Uncertain significance ★★ ⚠ same condition
CRYM c.325-12T>C Benign ★★ same condition
CRYM p.Thr288= Benign ★★ same condition
CRYM p.Tyr247= Benign ★★ same condition
CRYM p.Ala10Gly Uncertain significance ★ ⚠ same condition
CRYM p.Ala254Val Conflicting classifications of pathogenicity ★ ⚠ same condition
CRYM p.Ala303Thr Conflicting classifications of pathogenicity ★ ⚠ same condition
CRYM p.Glu175Val Conflicting classifications of pathogenicity ★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/crym-p-ile141val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown